Influenza, commonly known as the flu, is an infectious disease of birds and mammals caused by RNA viruses of the family Orthomyxoviridae, also known as the influenza viruses. Influenza spreads across the world in seasonal epidemics, resulting in millions of yearly cases of severe illness and hundreds of thousands of yearly deaths. In some outbreaks, the infection rates become pandemic. Often, new influenza strains appear when an existing flu virus spreads to humans from another animal species, or when an existing human strain picks up new genes from a virus that usually infects birds or pigs.
Influenza A, with its various subtypes (H3N2, H1N1, etc.) causes significant morbidity and mortality in humans and poses, for the foreseeable future, an significant threat of causing novel pandemics through genetic reassortments that can occur in other species such as birds and swine followed by transmission to humans.
Influenza A has been universally resistant to amantadine and rimantadine in recent years due to a mutation in the M2 proton channel drug target. The M2 protein is found in the viral envelope of influenza A virus and functions as a highly selective, pH-regulated proton channel important for the life cycle of the virus. Unlike neuraminidase inhibitors, rimantadine and amantadine are anti-viral agents capable of blocking the tetrameric M2 channel. In 2006, the U.S. Centers for Disease Control (CDC) issued an alert instructing clinicians to avoid using M2 ion-channel inhibitors during influenza season due to the extraordinarily high frequency of amantadine resistance in influenza A isolates associated with a single point mutation in the M2 protein, S31N. The drug-binding site is lined by residues that are mutated in amantadine-resistant viruses. Recently, it has been reported that resistance to rimantadine and amantadine in humans, birds and pigs has reached more than 90%, raising serious questions about the ability of these drugs alone to satisfy the need for treating influenza infections.
While some amantadine-like compounds have been found to be effective in vitro against influenza A, a persistent problem is the development of viral resistance to the potential therapeutic. Due to the propensity for M2 mutations, there has been very little investigation during the past 40 years into agents effective against the M2 target in influenza A. Since 2005, an amantadine- and rimantadine-insensitive S31N mutation has become highly prevalent in human influenza, abrogating clinical usefulness of amantadine and rimantadine. However, it has recently been recognized that the number of functional amantadine-insensitive M2 variations may be circumscribed to ˜5. Previous attempts by others have failed to identify drugs active against the currently pervasive mutant, S31N.
Accordingly, there is a need to develop therapeutic agents for the treatment of influenza infections, particularly emerging mutant strains such as those in the different subtypes of influenza A, as well as combination products better suited to avoid resistance development.